Single-cell expression analyses during cellular reprogramming reveal an early stochastic and a late hierarchic phase.

During cellular reprogramming, only a small fraction of cells become induced pluripotent stem cells (iPSCs). Previous analyses of gene expression during reprogramming were based on populations of cells, impeding single-cell level identification of reprogramming events. We utilized two gene expression technologies to profile 48 genes in single cells at various stages during the reprogramming process. Analysis of early stages revealed considerable variation in gene expression between cells in contrast to late stages. Expression of Esrrb, Utf1, Lin28, and Dppa2 is a better predictor for cells to progress into iPSCs than expression of the previously suggested reprogramming markers Fbxo15, Fgf4, and Oct4. Stochastic gene expression early in reprogramming is followed by a late hierarchical phase with Sox2 being the upstream factor in a gene expression hierarchy. Finally, downstream factors derived from the late phase, which do not include Oct4, Sox2, Klf4, c-Myc, and Nanog, can activate the pluripotency circuitry.

Oxytocin and the social facilitation of placebo effects.

Significant clinical improvement is often observed in patients who receive placebo treatment in randomized double-blind placebo-controlled trials. While a proportion of this "improvement" reflects experimental design limitations (e.g., reliance on subjective outcomes, unbalanced groups, reporting biases), some of it reflects genuine improvement corroborated by physiological change. Converging evidence across diverse medical conditions suggests that clinically-relevant benefits from placebo treatment are associated with the activation of brain reward circuits. In parallel, evidence has accumulated showing that such benefits are facilitated by clinicians that demonstrate warmth and proficiency during interactions with patients. Here, we integrate research on these neural and social aspects of placebo effects with evidence linking oxytocin and social reward to advance a neurobiological account for the social facilitation of placebo effects. This account frames oxytocin as a key mediator of treatment success across a wide-spectrum of interventions that increase social connectedness, thereby providing a biological basis for assessing this fundamental non-specific element of medical care.

Complex Interplay Between Cognitive Ability and Social Motivation in Predicting Social Skill: A Unique Role for Social Motivation in Children With Autism.

Impairment in social interaction is a core feature of autism spectrum disorder (ASD), but the factors which contribute to this social skill deficiency are poorly understood. Previous research has shown that cognitive ability can impact social skill development in ASD. Yet, children with ASD whose cognitive abilities are in the normal range nevertheless demonstrate deficits in social skill. More recently, the social motivation theory of ASD has emerged as a framework by which to understand how failure to seek social experiences may lead to social skill deficits. This study was designed to better understand the relationships between cognitive ability, social motivation, and social skill in a well-characterized cohort of children with ASD (n = 79), their unaffected siblings (n = 50), and unrelated neurotypical controls (n = 60). The following instruments were used: The Stanford-Binet intelligence quotient (IQ), the Social Responsiveness Scale's Social Motivation Subscale, and the Vineland Adaptive Behavior Scales' Socialization Standard Score. We found that lower cognitive ability contributed to diminished social skill, but did so universally in all children. In contrast, social motivation strongly predicted social skill only in children with ASD, such that those with the lowest social motivation exhibited the greatest social skill impairment. Notably, this relationship was observed across a large range of intellectual ability but was most pronounced in those with IQs ≥ 80. These findings establish a unique link between social motivation and social skill in ASD and support the hypothesis that low social motivation may impair social skill acquisition in this disorder, particularly in children without intellectual disability. LAY SUMMARY: The relationships between cognitive ability, social motivation, and social skill are poorly understood. Here we report that cognitive ability predicts social skill in all children, whereas social motivation predicts social skill only in children with autism. These results establish a unique link between social motivation and social skill in autism, and suggest that low social motivation may impair social skill acquisition in this disorder, particularly in those without intellectual disability.

Direct reprogramming of fibroblasts into embryonic Sertoli-like cells by defined factors.

Sertoli cells are considered the "supporting cells" of the testis that play an essential role in sex determination during embryogenesis and in spermatogenesis during adulthood. Their essential roles in male fertility along with their immunosuppressive and neurotrophic properties make them an attractive cell type for therapeutic applications. Here we demonstrate the generation of induced embryonic Sertoli-like cells (ieSCs) by ectopic expression of five transcription factors. We characterize the role of specific transcription factor combinations in the transition from fibroblasts to ieSCs and identify key steps in the process. Initially, transduced fibroblasts underwent a mesenchymal to epithelial transition and then acquired the ability to aggregate, formed tubular-like structures, and expressed embryonic Sertoli-specific markers. These Sertoli-like cells facilitated neuronal differentiation and self-renewal of neural progenitor cells (NPCs), supported the survival of germ cells in culture, and cooperated with endogenous embryonic Sertoli and primordial germ cells in the generation of testicular cords in the fetal gonad.

Neuroprotection and progenitor cell renewal in the injured adult murine retina requires healing monocyte-derived macrophages.

The death of retinal ganglion cells (RGCs) is a hallmark of many retinal neuropathies. Neuroprotection, axonal regeneration, and cell renewal are vital for the integrity of the visual system after insult but are scarce in the adult mammalian retina. We hypothesized that monocyte-derived macrophages, known to promote healing in peripheral tissues, are required after an insult to the visual system, where their role has been largely overlooked. We found that after glutamate eye intoxication, monocyte-derived macrophages infiltrated the damaged retina of mice. Inhibition of this infiltration resulted in reduced survival of RGCs and diminished numbers of proliferating retinal progenitor cells (RPCs) in the ciliary body. Enhancement of the circulating monocyte pool led to increased RGC survival and RPC renewal. The infiltrating monocyte-derived macrophages skewed the milieu of the injured retina toward an antiinflammatory and neuroprotective one and down-regulated accumulation of other immune cells, thereby resolving local inflammation. The beneficial effect on RGC survival depended on expression of interleukin 10 and major histocompatibility complex class II molecules by monocyte-derived macrophages. Thus, we attribute to infiltrating monocyte-derived macrophages a novel role in neuroprotection and progenitor cell renewal in the injured retina, with far-reaching potential implications to retinal neuropathies and other neurodegenerative disorders.